Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1204-12. doi: 10.1158/1055-9965.EPI-11-0059. Epub 2011 Apr 14.
Hispanic children have both a higher incidence and a poorer outcome in acute lymphoblastic leukemia (ALL). Moreover, a higher incidence for therapy-related acute myeloid leukemia with 11q23 translocations after treatment with topoisomerase II (topo II) inhibitors has been observed in Hispanic children with ALL. We sought to determine the potential role of genetic variants within the topoisomerase IIα gene (TOP2A), within the mixed lineage leukemia gene (MLL) and two of its translocation partners, cyclin AMP response element-binding protein gene (CREBBP) and E1A binding protein gene (EP300) in the increased sensitivity of Hispanic children with ALL to topo II inhibitors.
Fifty-two tagged single nucleotide polymorphisms (SNP) covering the four genes were genotyped in 241 samples (66 children with ALL and 175 age matched controls) of self-identified Hispanic origin.
Two SNPs within MLL (rs525549 and rs6589664) and three SNPs within EP300 (rs5758222, rs7286979, and rs20551) were significantly associated with ALL (P = 0.001-0.04). A significant gene-dosage effect for increasing numbers of potential high-risk genotypes (OR = 16.66; P = 2 × 10(-5)) and a major haplotype significantly associated with ALL (OR = 5.68; P = 2 × 10(-6)) were found. Replication in a sample of 137 affected White children and 239 controls showed that only rs6589664 (MLL) was significantly associated in this ethnic group.
Our findings indicate that the association between ALL and common genetic variants within MLL and EP300 is population specific.
Replication of our findings in independent Hispanic populations is warranted to elucidate the role of these variants in ALL susceptibility and define their importance in the ethnic specific differences in ALL risk.
西班牙裔儿童的急性淋巴细胞白血病（ALL）发病率更高，预后更差。此外，在接受拓扑异构酶 II（topo II）抑制剂治疗后，西班牙裔 ALL 儿童中观察到治疗相关急性髓系白血病伴 11q23 易位的发生率更高，这些易位与拓扑异构酶 IIα 基因（TOP2A）、混合谱系白血病基因（MLL）及其两个易位伙伴 cyclin AMP 反应元件结合蛋白基因（CREBBP）和 E1A 结合蛋白基因（EP300）内的遗传变异有关。我们旨在确定 ALL 中 topo II 抑制剂敏感性增加的西班牙裔儿童中，TOP2A 基因、MLL 及其两个易位伙伴 cyclin AMP 反应元件结合蛋白基因（CREBBP）和 E1A 结合蛋白基因（EP300）内的遗传变异的潜在作用。
在 241 个自我鉴定为西班牙裔的样本（66 名 ALL 患儿和 175 名年龄匹配的对照）中，对四个基因的 52 个标记单核苷酸多态性（SNP）进行了基因分型。
MLL 内的两个 SNP（rs525549 和 rs6589664）和 EP300 内的三个 SNP（rs5758222、rs7286979 和 rs20551）与 ALL 显著相关（P = 0.001-0.04）。发现潜在高危基因型数量增加的显著基因剂量效应（OR = 16.66；P = 2×10(-5)）和与 ALL 显著相关的主要单倍型（OR = 5.68；P = 2×10(-6)）。在 137 名受累白种儿童和 239 名对照的样本中进行的复制表明，只有 rs6589664（MLL）在该种族群体中显著相关。
我们的研究结果表明，ALL 与 MLL 和 EP300 内常见遗传变异之间的关联具有人群特异性。
在独立的西班牙裔人群中复制我们的发现，以阐明这些变异在 ALL 易感性中的作用，并确定它们在 ALL 风险的种族特异性差异中的重要性是必要的。
